The purpose of this K24 proposal is to allow the principal investigator to devote additional time to the development of innovative clinical therapeutics and patient-oriented correlative research projects. I have several NIH-funded patient-oriented research projects of my own, and am mentoring fellows and junior faculty in additional projects at the Vanderbilt Cancer Center. My own research involves a number of projects, all thematically related to the application of molecular biology to the treatment and analysis of cancer. Broadly, my proposal falls into four areas: 1) My main research focus involves the immunology of cancer, and specifically the development of immunotherapeutics and the study of cancer-associated immunodeficiency. I am running NCI CTEP-sponsored and RO3-funded clinical trials in immunotherapy, and mentoring a fellow whom is initiating two additional immunotherapy trials. We have recently demonstrated (with RO1 funding) defective DC function in human cancer patients, and that one of the factors responsible for this defect is tumor-derived vascular endothelial growth factor (VEGF). VEGF appears to signal through the flt-1 receptor on CD34+ hematopoietic progenitors, and its effects appear to be mediated by the transcription factor NF-kappaB. A head and neck surgical resident is performing these assays in head and neck and breast cancer in my lab (funded by another RO1 grant). We are developing inhibitors of the flt-1 receptor as novel therapeutics. 2) I also have an interest and history of publication in the gene therapy of cancer, with ongoing projects involving the inhibition of IGF1r signaling, and an NCI CTEP and ECOG sponsored gene therapy trial in lung cancer, run by medical oncology and pulmonary fellows and junior faculty under my supervision. 3) I have a long-standing interest and track record in the genetic analysis of human cancer and am mentoring a medical oncology fellow in my laboratory who is attempting to clone a novel chromosomal translocation associated with lung cancer in young people, and another fellow who is evaluating the role of bcl-2 in taxol responsiveness. 4) Lastly, as Director of the Experimental Therapeutics Program of the Vanderbilt Cancer Center, I am involved in the clinical development of a number of novel therapeutics and chemopreventive agents. This award would allow me additional time to further patient-oriented research at the, Vanderbilt Cancer Center and time to mentor fellow and junior faculty patient-oriented research projects.